Pfizer Seeks FDA Approval for Palbociclib

Pfizer has submitted a New Drug Application for palbociclib plus letrozole as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer, based on findings from the phase II PALOMA-1 trial.

The FDA will review the application within 60 days, at which point the agency will establish a review timeline for the novel CDK 4/6 inhibitor under the Prescription Drug User Fee Act. The fastest review under this program provides a decision within 6 months.

“Today’s submission marks an important milestone for Pfizer and palbociclib, and a potential advance for women with advanced breast cancer,” Garry Nicholson, president of Pfizer Oncology, said in a press release.

Inhibition of CDK 4/6 prevents DNA replication by prohibiting progression from G1 to S phase during cell division. Blocking this mechanism prevents tumor cell proliferation through control of the cell cycle. The rationale for the combination of an aromatase inhibitor with palbociclib stemmed from early preclinical evidence suggesting that CDK 4/6 is more active in patients with ER-positive breast cancer, as a result of an intact retinoblastoma (Rb)-pathway.

Palbociclib initially generated excitement at the 2012 San Antonio Breast Cancer Symposium when interim results from the PALOMA-1 trial demonstrated a dramatic improvement in progression-free survival (PFS) for the combination of palbociclib and letrozole versus letrozole alone. Based on these findings, the FDA granted palbociclib a breakthrough therapy designation in April 2013.

In the open-label PALOMA-1 study, 165 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer were randomized in a 1:1 ratio in two parts: Part 1 contained 66 patients and Part 2 had 99 patients. Continuous daily letrozole was administered at 2.5 mg with or without palbociclib at 125 mg daily for 3 weeks followed by 1 week of rest until progression. The primary endpoint was PFS by investigator assessment.

According to an update presented at the 2014 AACR Annual Meeting in April 2014, the median PFS was 20.2 months with palbociclib compared with 10.2 months for letrozole alone (HR = 0.488; P = .0004). The median overall survival (OS) was 37.5 months with palbociclib compared with 33.3 months with letrozole alone (HR = 0.813; 95% CI, 0.492-1.345; P = .2105). However, this first analysis of OS contained data from only 61 patients (37%) and was not deemed statistically significant.

The most commonly reported treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue. Neutropenia in the study was not cumulative and febrile neutropenia was not reported.

According to analysis presented at the 2014 ASCO Annual Meeting, palbociclib-induced neutropenia is generally short lasting and reversible with conservative management. This study combined safety data from 140 patients across two phase II studies of single-agent palbociclib in patients with various Rb-positive tumors. Overall, grade 3/4 neutropenia was present in 39% of patients. Grade 3 anemia occurred in 4% of patients and grade 3 thrombocytopenia was apparent in 9%.

A number of Pfizer-sponsored phase III clinical trials are exploring palbociclib as a treatment for patients with advanced breast cancer. Given the benefit demonstrated in the PALOMA-1 trial, these studies will be randomized in a 2:1 ratio favoring treatment with palbociclib

The PALOMA-2 trial is comparing the combination of palbociclib and letrozole with letrozole alone as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer (NCT01740427). The PALOMA-3 trial is comparing palbociclib plus fulvestrant against fulvestrant alone in women with HR-positive, HER2-negative metastatic breast cancer following progression on prior endocrine therapy (NCT01942135).

In addition to Pfizer sponsored studies, a number of investigator-led phase III trials have been established to explore palbociclib across a number of settings. These studies randomize patients in a 1:1 ratio to palbociclib in combination with hormonal therapy or chemotherapy.

The open-label phase III PEARL trial will compare exemestane plus palbociclib with capecitabine in HR-positive patients with metastatic breast cancer who are resistant to treatment with non-steroidal aromatase inhibitors (NCT02028507). The phase III PENELOPE-B trial will examine post-neoadjuvant treatment with palbociclib plus endocrine therapy in HR-positive patients with residual disease following chemotherapy and surgery (NCT01864746).